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Corneodesmosin: Structure, Function and Involvement in Pathophysiology Nathalie Jonca, Cécile Caubet, Marina Guerrin, Michel Simon and Guy Serre*

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Corneodesmosin: Structure, Function and Involvement in Pathophysiology Nathalie Jonca, Cécile Caubet, Marina Guerrin, Michel Simon and Guy Serre* 36 The Open Dermatology Journal, 2010, 4, 36-45 Open Access Corneodesmosin: Structure, Function and Involvement in Pathophysiology Nathalie Jonca, Cécile Caubet, Marina Guerrin, Michel Simon and Guy Serre* CNRS – University Toulouse III, UMR 5165 “Epidermis Differentiation and Rheumatoid Autoimmunity”, IFR 150 (INSERM-CNRS-University Toulouse III-CHU), France Abstract: Corneodesmosin (CDSN) was identified in the early 90th by raising monoclonal antibodies against human plantar stratum corneum. It is a protein specific to desmosomes that will undergo transformation into corneodesmosomes, i.e. in man, desmosomes of the epidermis, of the three epithelial layers of the inner root sheath of the hair follicles and of the hard palate epithelium. After its secretion by granular keratinocytes via the lamellar bodies, CDSN is incorporated into the desmoglea of the desmosomes shortly before their transformation into corneodesmosomes. CDSN displays adhesive properties, mostly attributable to its N-terminal glycine-rich domain, and is sequentially proteolyzed as corneocytes migrate towards the skin surface. The recent inactivation of Cdsn in mice induced a lethal epidermal barrier disruption and hair follicle degeneration related to desmosome dysfunction, confirming the essential role of the protein in epidermis and hair follicle integrity. CDSN is located on chromosome 6, in the major psoriasis susceptibility locus PSORS1. Intriguingly, the only monogenic disease identified so far associated with nonsense mutations in CDSN, leading to the formation of a truncated protein, is a rare autosomal dominant disease, hypotrichosis simplex of the scalp. In this review, we expose data from the discovery of the protein to the most recent findings related to the relationship between its structure and function. In particular, the important benefits of mouse models and human diseases for the comprehension of CDSN role in the epidermis and hair follicles are reported in details. Keywords: Corneodesmosome, corneodesmosin, cornification, desquamation, differentiation, epidermis, hyperkeratosis, hypotrichosis, kallikrein, psoriasis, stratum corneum. INTRODUCTION desmosomes in the SC, contributed to reconsider the place of proteins in the barrier function of the SC. The aim of epidermal differentiation is to produce an efficient barrier separating the body from the environment. This review focuses on CDSN. We expose the data from Such a role is fulfilled by the most superficial part of the the discovery of the protein to the more recent findings epidermis, the stratum corneum (SC). This layer is related to the relation between the structure and function of composed of corneocytes, which are dead and flattened CDSN. In particular, the important benefits of mouse models “mummified” cells endowed with a cornified envelope that and human diseases for the comprehension of the primordial provides extreme individual resistance. Owing to its relative role of CDSN in the epidermis and hair follicles are reported impermeability to water and water soluble substances, the in details. SC provides an efficient “inside-out” and “outside-in” CDSN: DISCOVERY OF A NEW PROTEIN SPECIFIC barrier. Its physical resistance and strong cohesion, TO THE LATE STEPS OF EPIDERMAL DIFFER- combined with its constant renewal, also offers a barrier ENTIATION against physical, chemical and microbial agents from the environment. In the 80th, the predominant model to explain In the early 90’s, Guy Serre’s group raised monoclonal the barrier function of the SC was the “brick wall” model antibodies against plantar SC in order to identify new late proposed by P. Elias, in which the corneocytes were the markers of epidermal differentiation. This led to the bricks endowed within an intercellular substance composed identification of CDSN, specifically recognized by two mostly of lipids. In the early 90th, emerging data suggested monoclonal antibodies, G36-19 and F28-27. Immuno- that the lipids, crucial for the barrier’s impermeability, histological studies indicated that CDSN is mainly expressed played only a limited part in tissue cohesion, whereas the in cornified epithelia, and is absent from the non-cornified integrity of the SC depended mostly on the corneocytes and epithelia of the vagina, uterine cervix, or esophagus [3]. In associated intercellular junctions. In particular, the finding addition, CDSN is present in the thymus Hassal’s bodies, that protease activity was necessary for desquamation to take containing epithelial cells very similar to differentiated place [1, 2], as well as the identification of corneodesmosin epidermal keratinocytes, and the CDSN gene was shown to (CDSN) as the only protein specifically localized in the be transcribed in the placenta by RT-PCR experiments [4]. extracellular part of corneodesmosomes [3], the modified CDSN is also expressed in the hair follicle. The protein appears asynchronously in the 3 compartments of the inner root sheath, as their cells cornify: first in the Henle’s layer, *Address correspondence to this author at the CNRS-UPS UMR5165, CHU then in the cuticle, and lastly in the Huxley’s layer [3, 5]. Purpan, Place du Docteur Baylac, TSA 40031, 31059 Toulouse Cedex 9, CDSN is also clearly detected in cells of the hair follicle France; Tel: 33 5 6115 8402; Fax: 33 5 6149 9036; E-mail: [email protected] medulla [4]. 1874-3722/10 2010 Bentham Open Corneodesmosin in Normal and Diseased Skin The Open Dermatology Journal, 2010, Volume 4 37 In the epidermis, as shown by immunohistology, CDSN covalent links. The nature of these covalent links, the is cytoplasmic in the lower stratum granulosum (SG) then it molecular partner -protein or lipid- involved in these links, becomes pericellular and progressively disappears in the as well as the enzyme responsible for the crosslink, remain lower SC. In contrast, the protein persists up to the unknown. Transglutaminases 1, 3 and 5 are responsible for desquamating keratinocytes in the palmoplantar epidermis the crosslink of the envelope precursor in the granular and hard palate epithelium, with a discontinuous keratinocyte. However, these enzymes are located in the pericorneocyte microgranular distribution. Similarly, CDSN cytosol or anchored to the internal side of the cytoplasmic is detected as surface spots on corneocytes isolated by membrane. No transglutaminase isoform was described to be scraping the hard palate or the epidermis. Immunoelectron secreted in the extracellular space, where it could use CDSN microscopy reveals that CDSN is present in the lamellar as a substrate. CDSN is the first and until now the only bodies from their emergence in the upper SG, in the protein specifically localized in the extracellular core of extracellular space of the desmosomes of the granular corneodesmosomes. This discovery contributed to the idea keratinocytes and lastly in the core of the modified that corneodesmosomes are not only desmosome remnants, desmosomes of the SC. Finally, CDSN was shown to be as considered until then, but fulfill a precise function in the largely preserved at the surface of purified cross-linked upper layers of the epidermis. envelopes, where it is located on fibrils gathered over the CDSN is a 52-56 kDa basic phosphoprotein. external side (Fig. 1). Moreover, as the envelopes were Deglycosylation experiments, reactivity to lectins, and purified under reducing and denaturing conditions, these data chromatography on concanavalin A-sepharose indicated that demonstrate that CDSN is covalently linked to the cornified it is N-glycosylated, with the oligosaccharide moiety envelope not only by disulfide bonds but also by other comprising ~10% of the protein mass [6]. Cloning of its Fig. (1). Localization of CDSN in human epidermis and hair follicle. (A) Immunolocalization of CDSN in human breast epidermis by indirect immunofluorescence. (B-D). Immunoelectron microscopy analysis reveals CDSN in lamellar bodies and in the intercellular part of desmosomes (arrow) of the granular keratinocytes (B) as well as in the core of corneodesmosomes in the SC (C). CDSN is also bound to the cornified cell envelopes (D). (E, F). Immunofluorescence staining on transversal (E) and longitudinal (F) sections of hair follicles shows a restricted labeling of CDSN in the three compartments of the inner root sheath: Henle’s layer (He), Huxley’s layer (Hu) and cuticle (cut), and in the medulla (med). Scale bars: 50 m (A), 200 nm (B, C), 100 nm (D), 20 m (E, F). In (A), nuclei were counterstained with Toto-3; dotted line, dermoepidermal junction. From references [3, 4] and unpublished data. Scale bars: 50 m (A), 200 nm (B, C), 100 nm (D), 20 m (E, F). In (A), nuclei were counterstained with Toto-3; dotted line, dermoepidermal junction. From references [3, 4] and unpublished data. 38 The Open Dermatology Journal, 2010, Volume 4 Jonca et al. encoding cDNA revealed that CDSN is located on CDSN displays adhesive properties mediated by its N- chromosome 6, in PSORS1, the major locus for psoriasis terminal glycine loop domain. susceptibility. The mRNA encodes a 529-amino acid protein with a N-terminal signal peptide and one putative N- THE PROGRESSIVE PROTEOLYSIS OF CDSN IN THE STRATUM CORNEUM IS A PRE-REQUISITE glycosylation site, consistent with the demonstration that it is secreted and glycosylated [7]. FOR DESQUAMATION As a step in elucidating the mechanisms of tissue-specific A tight balance between keratinocyte proliferation in the expression, the human CDSN promoter was characterized basal layer and cell shedding
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